Current Research

The eye is our window to the world and to the brain. The process of vision begins in the retina and in humans, the retina supplies almost 30% of the sensory input to the brain. Any damage to retinal neurons can lead to devastating consequences, including loss of vision. Retinal and macular diseases are a major cause of visual impairment and affect the quality of life of millions worldwide. The basic premise guiding research of the Retinal Development, Genetics & Therapy Section is that clinical manifestations of disease result from perturbations in normal cellular behavior and adaptive changes to genetic variants/mutations interacting with environmental factors. With a focus on the retina, our laboratory wishes to advance our understanding of several fundamentally important and interrelated biological processes and help pursue clinical interventions that exploit these advances. In particular, we seek to understand: (1) how neurons differentiate from neuroepithelial progenitors (or stem cells); (2) how these neurons form functional synaptic circuits; (3) how neuronal function is accomplished in the normal retina and how it is compromised during aging and in disease conditions; and (4) how we can repair the damage or treat the degenerative disease.

The following four “themes” encompass the many projects that we are developing in our lab:

Regulatory networks guiding retinal development, homeostasis and aging - One of our major efforts is to elucidate gene regulatory networks that guide differentiation of photoreceptor subtypes from retinal progenitor cells in vivo in the mouse retina and in vitro using human and mouse-derived embryonic (ESCs) and induced pluripotent stem cells (iPSCs). We are also focusing on the identification of molecules that control the specificity of photoreceptor synapse formation. Our work extends to the study of gene networks underlying photoreceptor homeostasis and aging. We apply cutting-edge genomic technologies (e.g., Next Generation Sequencing) to perform whole genome expression profiles, transcription factor binding and epigenetic studies.

Synaptic circuit formation in the retina

Genetic basis of human retinal disease—The genetic component of our laboratory is dedicated to the identification of genetic defects in inherited retinal degenerative diseases and genetic susceptibility variants associated with common multifactorial diseases (age-related macular degeneration, AMD, and diabetic retinopathy). We combine whole exome sequencing, targeted chip genotyping and well-established computational workflows for new disease gene discovery. We pursue the study of candidate genes to delineate molecular pathways leading to retinal pathology, focusing on retinal/macular degenerative diseases and on AMD. We take advantage of an extended colony of mouse models of retinal disease, zebrafish mutants, and we develop in vitro disease models using patient-derived iPSCs.

Treatment paradigms for retinal diseases—The ultimate goal of our laboratory is to develop treatment paradigms for retinal and macular degenerative diseases (specifically those caused by mutations in CEP290, RPGR and RP2), using a comprehensive set of approaches including pluripotent stem cells (ESCs and iPSCs), small molecules against specific gene or pathway-based targets, and gene replacement using viral vectors.

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